A controlled study of flumazenil-precipitated withdrawal in chronic low-dose benzodiazepine users

Rationale: Preclinical studies of the benzodiazepine antagonist flumazenil (Romazicon(R)) have contributed to the understanding of the physical depend ence associated with chronic benzodiazepine use; when administered to anima ls chronically pretreated with benzodiazepines, flumazenil precipitates a w ithdrawal syndrome. However, few controlled clinical studies have been cond ucted. Objectives: The objective was to characterize the effects of flumaze nil in long-term users of therapeutic doses of benzodiazepines. Methods: Th e acute physiological, participant-rated, and observer-rated effects of int ravenously administered flumazenil (1 mg/70 kg) and caffeine (300 mg/70 kg; active drug control) were evaluated in an experimental group of 13 long-te rm users (mean 4.6 years) of low therapeutic doses (mean 11.2 mg/day diazep am equivalent) relative to a matched group of 13 volunteers without prior e xposure to benzodiazepines in a double-blind, placebo-controlled, mixed des ign. Results: Whereas the experimental group did not differ from the contro l group with respect to the effects of placebo, and both groups showed some changes in response to caffeine (e.g., increased blood pressure and anxiet y scores), only the experimental group showed considerable changes in physi ological measures, participant ratings (e.g., increased ratings of dizzines s, blurred vision, heart pounding, feelings of unreality, pins and needles? nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch), and observer ratings in response to flumazenil; in a ddition, four participants developed panic attacks. Conclusions: This study clearly demonstrates that flumazenil can precipitate symptoms commonly ass ociated with benzodiazepine withdrawal in chronic low-dose benzodiazepine u sers.